Ischemic stroke

Ischemic stroke is an acute neurologic condition caused by impaired cerebral blood flow (e.g., vascular occlusion or systemic hypoperfusion). Chronic systemic hypertension and cardiovascular disease are the most important risk factors. Clinically, ischemic stroke is characterized by the acute onset of focal neurologic deficits, which are dependent on the cerebral territory covered by the relevant vessel. A noncontrast head CT should immediately be performed to rule out intracranial hemorrhage. Revascularization of the vessels affected in ischemic strokes, for example via tissue plasminogen activator (tPA) or thrombectomy, is vital to preserving brain tissue. Secondary prevention is focused on managing modifiable risk factors (i.e., hypertension, atherosclerosis).

For more information, see also transient ischemic attack, overview of stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.

• Stroke: acute neurologic injury caused by ischemia or hemorrhage
• Ischemic stroke: cerebral infarction due to insufficient cerebral blood flow (hypoperfusion), which results in ischemia and neuronal injury
• Transient ischemic attack: temporary, focal cerebral ischemia; that results in neurologic deficits without acute infarction or permanent loss of function (previously defined as lasting < 24 hours) ^[1]
• Hemorrhagic stroke: cerebral infarction due to hemorrhage
• Intracerebral hemorrhage: bleeding within the brain parenchyma
• Subarachnoid hemorrhage: bleeding into the subarachnoid space
• Intraventricular hemorrhage: bleeding within the ventricles

References:^[2][3][4]

• Ischemic strokes account for ∼ 85% of all strokes
• Nonmodifiable risk factors ^[5][6][7]
  • Age ≥ 65 years
  • Sex ♂ > ♀
  • Ethnicity: African Americans, Native Americans, Alaska Natives, and Hispanics are at higher risk.
  • Family history of cardiovascular or cerebrovascular disease
  • Genetic disorders (e.g., sickle cell disease)
  • History of TIA
  • Migraine with aura
• Modifiable risk factors ^[5][6]
  • Systemic hypertension
  • Hyperlipidemia
  • Diabetes mellitus
  • Atherosclerosis
  • Cardiovascular disease
    • Carotid artery stenosis
    • Atrial fibrillation
  • Obesity
  • Coagulopathy , hyperhomocysteinemia
  • Alcohol abuse
  • Tobacco use
  • Recreational drug use (e.g., cocaine can cause cerebral vasospasm)
  • Oral contraceptive use
  • Hormone replacement therapy

For both ischemic and hemorrhagic strokes, age is the most important nonmodifiable risk factor and arterial hypertension is the most important modifiable risk factor!

References:^[5][6][7]

Epidemiological data refers to the US, unless otherwise specified.

• Embolic strokes (∼ 20%)
  • Most commonly affect the middle cerebral artery (MCA)
  • Cardiac emboli
    • Atrial fibrillation
    • Atrial or ventricular thrombi
    • Rheumatic heart disease
    • Ventricular aneurysms
  • Atheroemboli
    • Internal carotid artery
    • Aortic arch (less common)
  • Infectious emboli: bacterial endocarditis
  • Paradoxical embolism; : in patients with right-to-left cardiac shunt (e.g., persistent foramen ovale or atrial septal defect)
• Thrombotic strokes (∼ 40%)
  • Large vessel atherosclerosis (∼ 20%)
    • Rupture of an atherosclerotic plaque and exposure of subendothelial collagen → formation of a thrombus
    • Thrombus formation most commonly occurs at branch points in arteries (e.g., internal carotid artery bifurcation or where the MCA branches from the circle of Willis).
  • Small vessel occlusion (e.g., lacunar infarct) (∼ 20%): see “Subtypes and variants” below.
• Global cerebral ischemia
  • Systemic hypoperfusion
    • Shock or bilateral large artery atherosclerosis (e.g., of carotid arteries) → decreased effective oxygen delivery to the whole brain
    • Can result in watershed infarct (see “Subtypes and variants” below)
  • Hypoglycemia: repeated episodes of hypoglycemia (e.g., due to insulinoma) increase the risk of cerebral ischemia
  • Severe and/or chronic hypoxia: hypoxemia (e.g., due to respiratory arrest) → global tissue hypoxia in the brain
• Other causes
  • Hypercoagulable states
    • Inherited thrombophilia (e.g., factor V Leiden mutation, protein C deficiency)
    • Polycythemia
    • Hormonal contraceptive use
    • Hormone replacement therapy
    • Sickle cell disease
  • Vasculitis (e.g., giant cell arteritis)
  • Arterial dissection (e.g., due to trauma or fibromuscular dysplasia)

References:^{[6][8][9][10][11][12][13][14][15]}

• Transient ischemic attack
• See differential diagnoses of stroke.

The differential diagnoses listed here are not exhaustive.

• Sudden onset of focal neurologic deficits (e.g., weakness/paralysis, paresthesias, aphasia, dysarthria)
• Nonspecific symptoms (e.g., impaired consciousness, nausea, vomiting, headache, seizures)
• Symptoms depend on the location of the stroke (see stroke symptoms by affected vessels and stroke symptoms by affected region)

Lacunar infarct ^[11][16]

• Definition: noncortical infarcts characterized by the absence of cortical signs (e.g., no aphasia, hemianopsia, agnosia, apraxia)
• Etiology
  • Most common: chronic hypertensive vasculopathy → lipohyalinosis of the small vessels → occlusion of small, penetrating arteries (e.g., lenticulostriate artery) → lacunar stroke resulting in specific lacunar syndromes (see lacunar syndromes)
  • Less common
    • Cardioembolic event
    • Microatheroma formation
    • Microbleed (rare)
• Risk factors
  • Hypertension
  • Diabetes mellitus
• Clinical features
  • Acute transient focal neurologic symptoms that often have a stuttering course
  • Symptoms depend on the affected territory.
    • See lacunar syndromes
    • Commonly affected areas
      • Internal capsule, corona radiata
      • Pons
      • Basal ganglia (striatum, putamen, globus pallidus, thalamus, caudate)
• Diagnosis: diffusion-weighted MRI
• Pathology: results in a pale infarction at the periphery of the cortex
• Treatment: same as other ischemic strokes; see “Treatment” below

Infarction of the posterior limb of the internal capsule is the most common type of lacunar stroke and may manifest clinically with pure motor stroke, pure sensory stroke (rare), sensorimotor stroke, dysarthria-clumsy hand syndrome, and/or ataxic hemiparesis.

Watershed infarct ^[6][17]

• Definition: border-zone infarct in the region between the territory of two major arteries that supply the brain (watershed area)
• Etiology: sudden decrease in blood pressure or cessation of blood flow through both vessels → ischemia in the susceptible region between two vascular territories
  • Cortical border zones: territories between the anterior and middle cerebral arteries and between the middle and posterior cerebral arteries
  • Internal border zones: territories between the superficial and deep branches of the MCA
• Clinical features
  • Signs of systemic hypoperfusion (e.g., tachycardia, low blood pressure, pallor, sweating)
  • Diffuse neurologic deterioration
  • PCA-MCA watershed region: Bilateral visual loss (cortical blindness)
  • ACA-MCA watershed region: Proximal limb weakness with sparing of the face, hands, and feet (“man-in-the-barrel syndrome”)

Patterns of necrosis in ischemic stroke ^[18]

• General: infarction → liquefactive necrosis → cystic cavity formation
• Two main responses to brain tissue ischemia
  • Selective neuronal necrosis: more likely to occur with transient ischemia
  • Pan-necrosis: more likely to occur with irreversible ischemia (e.g., infarction)
• Irreversible neuronal injury begins ∼ 5 minutes after tissue hypoxia
• See cellular changes and adaptive responses.

Infarction of brain tissue is typically followed by liquefactive necrosis, in contrast to the coagulative necrosis seen after infarction in other organs.

Selective neuronal necrosis

• Definition: selective destruction of nerve cells with sparing of glial cells
• Mechanism
  • Transient ischemia → subsequent reperfusion (e.g., resuscitation following cardiac arrest) → increased metabolic demand, release of toxic excitatory neurotransmitters → ischemic injury
  • Certain neurons are more susceptible to ischemic injury
    • Pyramidal cells of the hippocampus: Damage causes anterograde amnesia.
    • Purkinje cells of the cerebellum: Damage causes intention tremor, nystagmus, and ataxia.
    • Pyramidal cells of neocortex: Symptoms depend on the affected brain region.
• Histology: neuronal necrosis with viable glial cells (which can proliferate and cause a laminar or pseudolaminar tissue architecture)

Pan-necrosis

• Definition: the death of all cell types in a given region of the brain, including neurons, glial cells, and vascular cells
• Mechanism: permanent ischemia
• Histology: cystic lesions and loss of tissue architecture

Histologic changes in the infarcted region ^[18][19]

References:^[18][19]

Initial evaluation

• Determine the time of onset of symptoms: The time of stroke onset is used to determine treatment options (thrombolytic therapy).
• Stabilize the patient if needed.
• Check serum glucose.
• Emergency imaging

Imaging

1. Immediate noncontrast head CT to evaluate for acute hemorrhage prior to administration of thrombolytic therapy
2. Further choice of imaging depends on head CT findings.
   • Diffusion-weighted MRI is a more sensitive test for acute ischemia (e.g., if head CT is negative but clinical suspicion for acute stroke is high).
   • Neurovascular studies (e.g., CTA or MRA) for more specific identification of the occluded vessel

The decision to obtain further imaging should not delay the administration of thrombolytic therapy in appropriate candidates!

Noncontrast CT

• Ischemic changes can be detected ∼ 6 hours after stroke onset.
• Findings
  • Acute (within 12 hours of symptom onset)
    • Hyperdense occluded vessels (e.g., hyperdense MCA sign corresponding to acute thromboembolic occlusion of the MCA )
    • Hypodense parenchyma
    • Effacement of the sulci and loss of corticomedullary differentiation
  • 12–24 hours after symptom onset: hypodense
  • After 24 hours of symptom onset: hyperdense

Diffusion-weighted MRI

• Ischemic changes can be detected ∼ 3 minutes after stroke onset, but MRI takes longer to perform.
• Findings
  • T1: hypointense signal
  • T2: hyperintense signal

Neurovascular studies

• CT angiography (CTA)
  • Allows identification of the exact location of the defect (in most cases)
  • Indications
    • When there is a high index of suspicion for stroke but no ischemic changes are found on noncontrast CT or MRI.
    • If the patient cannot receive tPA (e.g., outside of the time window) but may be a candidate for mechanical thrombectomy (see “Treatment” below).
• MRI angiography (MRA): indications similar to CTA

Laboratory evaluation ^[20]

• Initial evaluation: serum glucose
• Subsequent laboratory tests to consider (after emergent imaging is complete)
  • Complete blood count, electrolytes, coagulation parameters (e.g., INR, APTT)
  • Serum troponin
  • Urine drug screen (e.g., cocaine), blood alcohol level
  • Serum lipids
• Hypercoagulable workup: consider if patient is < 50 years old and/or has a history of thrombosis
  • Protein C and protein S
  • Antiphospholipid antibodies
  • VDRL/RPR
  • Lyme serology
  • Factor V Leiden mutations
  • ANA
  • ESR
  • Rheumatoid factor

Immediate imaging or administration of tPA for ischemic stroke should not be delayed to obtain laboratory studies!

Additional diagnostic workup

• ECG to rule out atrial fibrillation and myocardial ischemia
• Continuous cardiac rhythm monitoring for paroxysmal atrial fibrillation
• Transthoracic echocardiogram (TTE) and/or transesophageal echocardiogram (TEE) to evaluate for intracardiac thrombus and patent foramen ovale (PFO)
• Carotid ultrasound to evaluate for carotid artery stenosis

For more information on the diagnosis of other stroke types, see diagnosis of stroke.

References:^{[13][15][20][21]}

Reperfusion therapy

• Goal is to prevent further tissue ischemia and irreversible infarction
• Should be administered as soon as possible in eligible candidates (see below for specific indications)

Reperfusion therapy should not be delayed – “time is brain”! However, intracranial hemorrhage is a contraindication for reperfusion therapy and must be ruled out first.

IV thrombolytic therapy ^[20]

• Definition: administration of intravenous recombinant tPA (e.g., alteplase, tenecteplase) to break down blood clots
• Indications
  • Acute ischemic stroke after ruling out intracranial hemorrhage
  • Initial onset of symptoms ≤ 4.5 hours ^[20]
  • Age ≥ 18 years
• Complications
  • Bleeding
  • Intracranial and extracranial hemorrhage
  • Angioedema
• Exclusion criteria
  • Current conditions
    • Intracranial bleeding
    • Active internal bleeding or bleeding diathesis
    • Hypertension > 185/110 mm Hg
    • Anticoagulation (prolonged PTT or INR > 1.7)
    • Low platelet count
    • Hypoglycemia < 50 mg/dL or hyperglycemia > 400 mg/dL
    • Minor stroke or TIA
  • Preexisting conditions
    • Previous intracranial hemorrhage
    • Head trauma or ischemic stroke (within the past 3 months)
    • Recent intracranial or intraspinal surgery
    • Arterial puncture at a noncompressible site (within the past 7 days)
    • Intracranial neoplasm, arteriovenous malformation, or aneurysm

Intra-arterial thrombolysis ^[20]

• Definition: intra-arterial (not intravenous) administration of a thrombolytic agent (e.g., prourokinase)
• Indication: MCA stroke patients with onset of symptoms < 6 hours who are not eligible for IV thrombolytic therapy

Mechanical thrombectomy ^[20]

• Definition: physical retrieval of the occluding thrombus via a catheter (usually through the femoral artery)
• Indications: proximal large artery occlusion in anterior cerebral circulation (usually in addition to intravenous thrombolytic therapy)

Blood pressure management ^[20]

• Elevated blood pressure is generally tolerated in acute ischemic stroke (permissive hypertension).
• For patients with severe hypertension (> 220 mm Hg / > 120 mm Hg)
  • Patients who do not undergo thrombolytic therapy: Reduce blood pressure by ∼ 15% within the first 24 hours of stroke onset.
  • Patients who undergo thrombolytic therapy: Reduce blood pressure to ≤ 185 mm Hg / ≤ 100 mm Hg prior to administering tPA.

Supportive care

• See “Treatment” in overview of stroke.

Other

• Prevent post-stroke complications (see “Complications” in overview of stroke)
• Secondary prevention (see below)
• Early rehabilitation (physiotherapy, occupational and speech therapy) and mobilization

References:^{[9][10][15][20][22][23][24][25][26]}

• Determine the time of onset of symptoms and assess score on stroke scale.
• Immediate neurology consult/stroke code
• Establish IV access.
• Immediate head CT without contrast (to rule out hemorrhage)
• Consider further imaging (e.g., MRI or CTA with or without perfusion protocol).
• Evaluate indications and contraindications for thrombolytic therapy.
• If indicated, administer thrombolytic therapy (e.g., alteplase ). ^[20]
• Blood pressure management
  • Exclude high-grade stenosis of the brain-supplying arteries before reducing blood pressure.
  • For patients with severe hypertension (> 220 mm Hg / > 120 mm Hg):
    • Patients not undergoing thrombolytic therapy: Reduce blood pressure by ∼ 15% within the first 24 hours of stroke onset.
    • Patients undergoing thrombolytic therapy: Reduce blood pressure to ≤ 185/100 mm Hg prior to administering tPA and keep it under this level for the following 24 hours.
  • Preferred agents ^[20]
    • Labetalol
    • Nicardipine
    • Clevidipine
• Evaluate indication for mechanical thrombectomy of proximal vessel occlusion.
• Identify and treat the underlying cause (e.g., TTE if concern for embolic stroke).
• Identify and treat any complications (e.g., seizures, increased ICP).
• Admit to neurology or medicine service.
• Make patient NPO and order dysphagia screening.
• Order physical therapy and occupational therapy.
• Close observation, GCS monitoring, and serial neurologic examination
• Electrolyte repletion
• Euglycemia: Avoid hypoglycemia and hyperglycemia.
• Normothermia: antipyretics for fever
• Normovolemia: IV fluids for hypovolemia
• VTE prophylaxis

• See “Complications” in overview of stroke.
• Embolic strokes are more likely to undergo hemorrhagic conversion than thrombotic strokes.

We list the most important complications. The selection is not exhaustive.

• Primary prevention: management of modifiable risk factors to decrease the likelihood of having a first stroke ^[27]
  • Healthy diet
  • Physical activity
  • Weight loss
  • Smoking cessation
  • Medical management of risk factors (e.g., hypertension, diabetes, atrial fibrillation, dyslipidemia)
• Secondary prevention ^[12][20]
  • Antiplatelet therapy (e.g., aspirin or clopidogrel)
    • Start 24–48 hours after symptom onset of ischemic stroke
    • Contraindicated for 24 hours after thrombolytic therapy
  • Medical management of risk factors
    • Hypertension: lifestyle modifications, antihypertensive medications
    • Atrial fibrillation: anticoagulation (e.g., warfarin)
    • Diabetes mellitus; : lifestyle modifications, glycemic control
    • Hyperlipidemia; : lifestyle modifications, statin therapy
    • Thrombophilia: anticoagulation
  • Medical management and/or carotid endarterectomy for carotid artery stenosis

The single most important treatable risk factor for secondary stroke prevention is hypertension! ^[12]

References:^[12][22][28]

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